An evaluation of phase I clinical trial designs in the continuous dose-response setting.

Abstract

Both traditional phase I designs and the increasingly popular continual reassessment method (CRM) designs select an estimate of maximum tolerable dose (MTD) from among a set of prespecified dose levels. Although CRM designs use an implied dose-response model to select the next dose level, in general it is neither assumed nor necessary that this model be tied to the actual dose of a drug. In contrast, in our two-stage design the fitting of a dose-response model after data have been collected is a necessary feature of the design, and the MTD is not constrained to be one of the prespecified dose levels. We conducted a simulation study to evaluate the performance of the two-stage design, two likelihood-based CRM designs, and two traditional designs in estimating the MTD in situations where one assumes that an explicit dose-response model exists. Under a wide variety of dose-response settings, we examined the bias and precision of estimates, and the fraction of estimates that were extremely high or low. We also studied the effect of adding a model fitting step at the end of a traditional design or a CRM design. The best performance was achieved using the two-stage and CRM designs. Although the CRM designs generally had smaller bias, the two-stage design yielded equal or somewhat smaller precision in some cases. The addition of a model-fitting step slightly improved the precision of the CRM estimates and decreased the percentage of extreme estimates. Allowing interpolation between doses for updating during CRM did not improve overall performance.